In the United States duodenal ulcer disease remains an important cause of substantial morbidity and economic cost. The pathogenesis of duodenal ulcer is not fully understood. However, duodenal mucosal bicarbonate production is likely an important defensive factor that protects the duodenum from acid-peptic damage; and, recent evidence suggests that the duodenal bulb in patients with inactive ulcer demonstrates impaired resting and H+-stimulated bicarbonate production. This proposal will focus on three separate, yet interrelated, areas. First, in patients with inactive duodenal ulcer: a) prostaglandin E2 output from the proximal duodenum will be contrasted with normal subjects (PGE2 is a potent agonist of bicarbonate production, and likely involved with the H+-induced bicarbonate response.), b) proximal duodenal mucosal structure will be determined by quantitative light and electron microscopy and contrasted with mucosal function (bicarbonate secretion, carbohydrate absorption, and disaccharidase activity), c) assess whether the impaired bicarbonate response represents a generalized defect of the duodenal bulb and therefore the effect of other agonists will be determined (e.g, PGE2, VIP), d) bicarbonate production will be related to ulcer activity. Second, the mechanisms that regulate human duodenal bicarbonate secretion will be examined both in vivo and in vitro. Third, the actions and interactions of agents that regulate human duodenal bicarbonate production will be assessed. In vivo human studies will be complimented by in vitro studies of duodenal bicarbonate transport. These experiments will provide fundamental as well as clinically relevant information regarding human duodenal bicarbonate production in health and disease. The relationship between structure and function will be clarified. And, an understanding of the precise mechanisms and agents that regulate proximal duodenal ion transport will serve as a basis for advances in knowledge of the physiology and pathophysiology defensive factors of the human duodenal bulb, mucosal defense, and duodenal ulcer disease.